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Strategy for Liver Failure by Regulating Hepatic Microcirculation through Hepatic Stellate Cell Activatity

通过肝星状细胞活性调节肝微循环治疗肝衰竭的策略

基本信息

批准号：
12470238
负责人：
SHIMAHARA Yasuyuki
金额：
$ 9.09万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470238/
关键词：
hepatic stellate cell hepatic microcirculation Liver failure Intravital microscopyu Liver fibrosis ROCK Rho kinase inhibitor Y-27632 enndotoxin 類洞壁細胞肝障害虚血再潅流障害

项目摘要

Hepatic stellate cell is known to regulate hepatic sinusoidal blood flow through its contraction and relaxation. When it is contracted by activation, sinusoidal blood flow is reduced. Therefore, it is considered that regulation of activation of hepatic stellate cell can be a potential strategy to improve hepatic microcirculation. We have clarified in TAA-induced cirrhosis model of rats that N-acetyl-L-cysteine (NAC) has a powerful effect on prevention of hepatic stellate cell activation and progress of fibrosis. In such model, microcirculation was well maintained. Rock/Rho kinase inhibitor, Y-27632 is also known to prevent activation of hepatic stellate cell and prevent fibrosis. In this series of the study, we have examined whether Y-27632 has an effect on improvement of hepatic microcirculation. We have investigated it in ischemia/reperfusion model of rat liver using hemHateral clamp of the.liver. Y-27632 protected ischemia/reperfusion induced injury of the liver through remarkable improvement of hepatic microcirculation, which was observed by intravital microscopy. Diamiter of sinusoid and postsinusoidal venule , sinusoidal perfusion rate were maintained as compared to sham group. Adherence of leucocytes in the sinusoid and postsinusoidal venule was much less, which results also in protection of disturbance of the blood flow. Y-27632 also exhibited to improve disturbance of microcirculation due to endotoxemia.

肝星状细胞通过收缩和舒张调节肝窦血流。当它被激活收缩时，正弦血流减少。因此，调控肝星状细胞的活化可能是改善肝脏微循环的一个潜在策略。我们已经在TAA诱导的大鼠肝硬化模型中阐明了N-乙酰-L-半胱氨酸（NAC）对防止肝星状细胞活化和纤维化进展具有强大的作用。在该模型中，微循环得到良好维持。Rock/Rho激酶抑制剂Y-27632也已知可防止肝星状细胞的活化并防止纤维化。在这一系列的研究中，我们检查了Y-27632是否具有改善肝脏微循环的作用。我们用大鼠肝缺血再灌注模型，用肝动脉钳夹法观察了它的变化。用活体显微镜观察Y-27632对肝脏缺血再灌注损伤的保护作用，发现其机制可能与改善肝脏微循环有关。与假手术组相比，窦状静脉和窦后小静脉内径、窦状静脉灌注率均保持不变。白细胞在窦状隙和窦后小静脉中的粘附少得多，这也导致对血流障碍的保护。Y-27632还表现出改善内毒素血症引起的微循环障碍。